Tlr7/8 antagonists for the treatment of coronavirus infections

Abstract

TLR7/8 antagonists can be used to treat coronavirus infections, including COVID-19, alone or in combination with one or more additional therapeutic agents.

1 . A method, of treating a coronavirus infection in a subject in need thereof, comprising:
 administering an effective amount of a TLR 7/8 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.   
     
     
         2 . The method of  claim 1 , wherein the coronavirus causes a SARS or MERS infection. 
     
     
         3 . The method of  claim 1 , wherein the coronavirus causes a SARS-CoV1 or SARS-CoV-2 or MERS-CoV infection. 
     
     
         4 . The method of  claim 1 , wherein the coronavirus is SARS-CoV-2. 
     
     
         5 . The method of  claim 1 , wherein the TLR 7/8 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the TLR 7/8 inhibitor is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the subject is suffering from a hyperinflammatory host immune response to a SARS-CoV-2 infection. 
     
     
         8 . The method of  claim 1 , wherein the subject has COVID-19 pneumonia. 
     
     
         9 . The method of  claim 1 , wherein the subject has a moderate to severe COVID-19 which requires medical intervention. 
     
     
         10 . The method of  claim 7 , wherein the hyperinflammatory host immune response is associated with one or more clinical indications selected from the group consisting of 1) reduced levels of lymphocytes; 2) high levels of inflammatory parameters and pro-inflammatory cytokines; 3) a deteriorating immune system demonstrated by lymphocytopenia and/or atrophy of the spleen and lymph nodes, along with reduced lymphocytes in lymphoid organs; 4) dysfunction of the lung physiology represented by lung lesions infiltrated with monocytes, macrophages, and/or neutrophils, but minimal lymphocytes infiltration resulting in decreased oxygenation of the blood; 5) acute respiratory distress syndrome (ARDS); 6) vasculitis; 7) encephalitis; Guillain-Barre syndrome, and other neurologic disorders; 8) kidney dysfunction and kidney failure; and 9) hypercoagulability such as arterial thromboses; and 10) any combination of above resulting in end-organ damage and death. 
     
     
         11 . The method of  claim 1 , wherein the subject is an adult patient. 
     
     
         12 . The method of  claim 1 , wherein the subject is a pediatric patient. 
     
     
         13 . The method of  claim 12 , wherein the pediatric patient is suffering from vasculitis. 
     
     
         14 . The method of  claim 1 , wherein the TLR 7/8 inhibitor is administered once or twice a day. 
     
     
         15 . The method of  claim 1 , wherein the total amount of TLR 7/8 inhibitor administered is between about 50 mg and about 300 mg per day. 
     
     
         16 . The method of  claim 1 , wherein 50 mg or 100 mg of the TLR 7/8 inhibitor is administered twice a day. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the TLR 7/8 inhibitor is administered for about 7 days to about 21 days. 
     
     
         19 . The method of  claim 18 , wherein the TLR 7/8 inhibitor is administered for about 14 days. 
     
     
         20 . The method of  claim 1 , wherein 100 mg of the TLR inhibitor is administered twice a day to the subject in need thereof for 14 days. 
     
     
         21 . The method of  claim 1 , wherein the TLR 7/8 inhibitor is administered orally. 
     
     
         22 - 71 . (canceled)